9alpha-halo-21-aldo-steroids of the pregnane series



United States Patent 9a-HALO-2l-A'ILDO-STEROIDS OF PREGNANE SERIES Josef Fried and Josef E. Herz, New Brunswick, N.J., as-

signors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia N0 Drawing. Filed Jan. 20, 1955, Ser, No. 483,166

12 claims. (Cl. 260-23955) steroids.

One of the objects of this invention is the provision of an advantageous process of preparing steroids of the pregnane (including the pregnene and allopregnane) series having a 2l-aldo or acetalized or diesterified aldo group, a 9u-halo group, and an llfl-hydroxy or ll-keto group.

Another object of this invention is the provision of steroids of the pregnane (including the pregnene and allo= pregnane) series having a 17a-hydroxy group, a 21-aldoor acetalized or diesterified aldo group, a 9a-halo group, and an llfi-hydroxy or ll-keto group, which compounds are useful either for their own physiological action or as intermediates in the re aration of physiological-active derivatives.

Still another object of this invention is the provision of steroids of the pregnane (including pregnene and allopregnane) series having an 18-aldo group, -a 2l-aldo or acetalized or diesten'fied aldo group, a 9a-halo group, and an llfi-hydroxy or ll-keto group.

A further object of this invention is the provision of steroids of the pregnane (including pregnene and allopregnane) series having a 17u-hydroxy group, a 21-aldo or acetalized or diesterified aldo group, and a 9,8,11floxido group, which compounds are useful intermediates in the preparation of physiological active derivatives.

Yet another object of this invention is the provision of novel intermediates useful in the preparation of the 21- aldo or acetalized or diesterified aldo steroids of this invention.

The 9a-halo compounds ofthis invention comprise: (a) the steroids of the pregnan'e (including the pr'egrijeiie and allopregnane) series havinga 17u-hydroxy substituent, a 21-aldo or acetalized or diesterified aldo substitue ent, a 9ix-halo substituent, and an ll 8-hydroxy or 11-keto substituent; and (b) the steroids of the pregnane (including'pregnene and allopregnane) series, unsubstituted in the 17-position, and having a 9a-halo substituent, an 115- hydroxy or ll-keto substituent, and 18-aldo substituent, and a 21-aldo or ace'talized or diesterified aldo substituent. These new steroids are prepared by one of the processes of this invention, which essentially comprises converting a 9a-halo, llfi-hydroxy or ll-keto, 21-hydroxy steroid of the pregnane (including pregnene and allopregnane) series to the corresponding 21-desoxy-21-quaternary ammonium salt, thence to a 21-desoxy-2l-nitrone derivative, then converting the nitrone to either the 21-aldehyd'e derivative or 21-acetal derivative by reaction with an acid or an acid in alcohol, respectively, andthen optionally,

converting the ZI-aldehyde derivative to either a 21- acetal derivative or a 21-diester derivative. [The diesters of aldehydes referred to herein are, of course, diesters of the hydrate form of the aldehydes, such reference being conventional.]

2,972,610 Patented Feb. 21, 1961 ice r 2 9a-halo and a-21 a1do group are: (a) those of the general formula v and (b) those of the general formula This invention relates to the synthesis of valuable O=CH CH=O

wherein the 4,5 position is double-bonded or saturated (preferably double-bonded), andwherein R is hydrogen, R is hydroxy or together R and R is a keto or ketalized keto group (preferably the free keto group), R is hy drogen, R, is fi-hydr'oxy, or together R" and R'" is a keto group, and X is an a-halogen group. ence of a hydroxy-containing solvent (e.g. water), the 21-aldo group readily adds a mole of the "solvent, and, therefore, exists as a hydrate (or equivalent), the terms 21-aldo and 21-aldehyde are hereby defined as including such derivatives as the hydrate, but not as including the acetal derivatives, which are referred to as acetalized'aldo or aldehyde, or the diester derivatives, which are referred to as die'sterified aldo or aldehyde] Representative 21-aldo steroids of this invention in"-' clude: 9wlfluoro-A pregnene-1lfi,17u-dio1-3,20-dione-2la1; 9a-chloro-A -pregnene 11,8,17a-diol-3,20-dione-21-al; 9a-bromo-A -pregnene-"1 1B,17a-diol-3,20-dione-21-al; 9aiodo-M-pregnene-I113,17 x-diol-3,20-dione-21-al; 9a-fiuoro- A -pregnene 17a-ol -3,1 1',20 trione-21-al; 9a chloro-A pregnene-17u-ol-3,11,20-trione=21-al; 9a bromo-A -pregnene-17a-ol-3,1 1,20-trione-2 1-al; 9aiodo-A -pregnene-17a 9a-halo and a 21-acetal group are: (a) those of the gen-- eral formula wherein the 4,5 position is double-bonded or saturated Among the compounds of this invention which have a (preferably double-bonded). and. wherein R, R, R", R"

[Since, in the pres-' and X are as above-defined, and Y is either of the acetalized aldo groups 018 ==C or C wherein B is a saturated aliphatic radical, such as an alkyl (e.g. a lower alkyl, such as methyl, ethyl, propyl, n-butyl or amyl), a haloalkyl (eg a halo-substituted lower alkyl, such as chloromethyl, 2-fluoroethyl, 2-brornopropyl, or l-2-dichloroethyl), or an alkoxyalkyl (e.g. a lower alkoxyalkyl, such as ethoxymethyl, methoxyethyl, or ethoxyethyl); or B is an aralkyl radical such as a phenylalkyl (e.g. benzyl, phenethyl, tolyethyl, p-chlorobenzyl, or anisylmethyl), or a naphthylalkyl (e.g. naphthylmethyl); and B is a saturatedv aliphatic divalent radical such an alkylene (e.g. a lower alkylene, such as ethylene, propylene, Z-methylpropylcne, or butylene), a haloalkylene (e.g. a halo-substituted lower alkylene, such as chloroethylene, fluoropropylene, or Lchloro-Z-ethylpropylene), or an alkoxyalkylene (eg a lower alkoxylower-alkylene, such as ethoxyethylene, 2-methoxypropylene, or methoxyethylene); and (b) those of the general formula O=CH wherein the 4,5 position is double-bonded or saturated, and wherein R, R, R", R" X, and Y are as abovedefined. [The preferred compounds (b) are those wherein the 4,5-position is double-bonded, R and R together represent oxo, R is hydrogen, and R" is {i-hydroxyJ Representative 9oz-hal0, acetalized 21-aldo steroids of this invention include the acetals (both straight chain and cyclic) of the hereinbefore-named specific aldehydes.

Among the compounds of this invention which have a 9a-halo and a 21-diester group are (a) those of the genwherein the 4,5 position is double-bonded or saturated (preferably double-bonded), and wherein R, R, R", R" X, and B are as above-defined, and (b) those of the general formula 4 wherein the 4,5 position is double-bonded or saturated, and wherein R, R, R", R" X, and B are as abovedefined. [The preferred compounds (b) are those wherein R and R together represent oxo, R" is hydrogen, and R" is /8-hydroxy.]

Representative 9a-halo diesterified 2l-aldo steroids of this invention including the diesters of the hereinbeforenamed specific aldehydes. The particularly preferred compounds are those wherein B is a lower alkyl radical (eg the diacetates).

According to one of the processes of this invention,

a steroid of the pregnane (including pregnane and allopregnane) series having a 21-hydroxy group, a 9a-halo group, and an llfi-hydroxy or ll-keto group is reacted with an aromatic sulfonyl halide (e.g. an aromatic sulfonyl chloride or sulfonyl bromide) in the presence of a tertiary base. The product initially formed will depend upon the temperature of the reaction. At a low temperature in the range of about -10 C.' to about +l5 C. (preferably about 10 C. to 15 C.), the 2l-hydroxy group is initially replaced by the halide moiety of the sulfonyl halide, yielding the corresponding steroid of the pregnane series having a 21-halo group (e.g. chloro or bromo), a 9a-halo group, and an 11/8-hydroxy or 11- keto group. However, if the temperature of the reaction is elevated to the range of about 40 C. to about 100 C. (preferably about C. to C.), or the initial reaction is carried out at low temperature and the 2l-halo formed is reacted with excess tertiary base at the elevated temperature, a quaternary ammonium salt of the 21-halo steroid and the tertiary base is formed as the principal product.

Among the compounds which are suitable as initial reactants in the foregoing process are those of the general formula wherein the 4, S-position is double-bonded or saturated, A is methyl or formyl, Z is hydrogen or u-hydroxy, and R, R, R", R" and X are as hereinbefore-defined. The preferred compounds are those wherein the 4, 5- position is double-bonded, R and R together represent 0x0, R" is hydrogen, R" is B-hydroxy, or together R" in the presence of a tertiary base, such as pyridine, a

lutidine, or a collidine [although other tertiary organic bases such as tri (lower alkyl) amines mayalso be used] either in-the cold or at elevated temperatures. If the reaction is conducted at a low temperature, then a 21-ha1o steroid: formed. Thesecompounds are exemplified by those of the following general formula wherein the 4, S-position is doubled-bonded or saturated (preferably double-bonded) ,1 X is 'cjhloro or bromo (preferably chloro), and R, R, R", R", A, Z- and X'are as above-defined. v V v Representative compounds include-: the- 9a,21-dihalo- (wherein the 21-halo is limited to either chloro or bromo) -A -pregnene-1 1B,17a-diol-3,20-diones in our US. application Serial No. 434,672, filed June 4,

[disclosed (preferably double-bonded), R, R, R", R', A, Z, and

- hol of the formula BOH or a dihydric alcohol of the formula B'(OH) wherein B and B are as above-defined, preferably with an alcohol of the formula BOH, wherein B is a lower alkyl (e.g., methyl, ethyl, n-propyl, or nbutyl) or benzyl radical. The reaction is preferably rcarriedout by dissolving or suspending the starting material in an anhydrous organic solvent, such as chloro- 1954, now US. Patent No. 2,263,671]; the 9a-halo-21- chloro-M-pregnene-17a-ol-3,11,20-triones; the 9a-halo-21- bromo-M-pregnene-l7a-ol-3,11,20-triones; the 9a-halo- 21-chloro-A -pregnene-11}3-ol-3,20-diones; the 9u-halo- 21-bromo-A -pregnene-11;3-ol-3,20-diones; the 9a-halo- 21-chloro-A -pregnene-3,11,20-triones; the 9a-halo-2lbromo-A -pregnene-3,11,20-triones; the 9a-halo-2l-chloro- M-pregnene-l1B-ol-3,20-dione-IS-als; and the 9a-halo 21- bromo-A pregnene-l 1fl-ol-3,20-dione-18-als.

If the starting materials, or the 21-halo derivatives thereof (which may be formed by conducting the reaction at a low temperature) are reacted with the tertiary base at elevated temperature, a ZI-quaternary ammonium halide (wherein the halide is bromide or chloride)" is formed. These quaternary ammonium salts are exemplified by those of the following general formula R m is) a; 5 WW jz j g/ v w l'fiin the 4, 5-position is double-bonded or saturated mole of steroid.

form, acetone, dioxane, etc., and treating the solution with a mineral acid such as hydrogen chloride or a strong organic acid, such as trichloroaeetic acidj or p-toluene sulfonic acid, dissolved in the alcohol reactant. The ratio of alcohol to steroid for the reaction is preferably at least two equivalents of alcohol (i.e. two moles of analcohol BOH or one mole of an alcohol B'(OH) per If the alcohol reactant is a lower alcohol, the nitrone can be suspended directly in the mineral acid-alcohol solution, thereby eliminating the organic solvent. The reaction proceeds readily at room temperature, but may beconducted at any temperature in the range of about 25 C. to about C.

The acetal derivative formed by this step of the process of this invention may then be converted to the corresponding free aldehyde by reactingthe acetal with an aqueous mineral acid, such as hydrochloric acid or perchloric acid, in mixture with an'organic solvent, such as acetic acid, dioxane, acetone, etc., preferably at room temperature. V

The free aldehydes can also be prepared directlyfrom the nitrones by reacting the latter with the aforementioned mineral acids or strong organic acids, in an inert organic solvent such as acetone, acetic acid, dioxane, etc., preferably at room temperature. These free aldehydes can then in turn be converted to either the acetalized derivatives by treatment with an alcohol, such as those of the formula BOH and B'(OH) under acidic conditions,

or the diesterified derivatives by treatment, in an organic base (e.g. pyridine), with an anhydride, such as those of the formula g wherein B is as hereinbefore-defined, as exemplified by acetic anhydride.

A modification of the process of this invention consists of the direct oxidation of an acetal derivative of a 21-aldo steroid having an llfi-hydroxy group to the corresponding acetal derivative having an ll-keto group. Thus, to form a 21-aldo steroid having an ll-keto group, instead of starting with the corresponding steroid having an ll-keto group and converting this ll-lceto steroid to acetal derivative and thence to the free aldehyde, the llfi-hydroxy derivative (R is hydrogen, R is ,s-hydroxy) is chosen as the initial reactant, and this reactant is converted to the 21-acetal derivative. The acetal derivative is then reacted with a customary oxidizing agent, such as chromic oxide in a basic medium such as pyridine, to oxidize the llfi-hydroxy group to keto, and the ll-keto 21-acetal derivative thus formed is then converted to the free 21-aldehyde.

For the purpose of illustrating one process of this invention, reference is made to the following schematic analysis employing Qua-halo-hydrocortisone and Qua-halocortisone as starting materials:

H (aqueous acetone) 3 OH OH 0B 0g 0% l 0B 0B c= R!!! ""OH RI" L---0H RH RI! /I B OH 1': 1': 0: (acetone) 0- The acetal derivatives, the diester derivatives, and the 65 free aldehydes of this invention are active materials which possess glucocorticoid as well as mineralocorticoid activity. Thus, the new steroids of this invention can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatornyositis, and desoxycorticosterone in the treatment of Addisons disease or adrenal insufiiciencies. The dosage for such administration is of course dependent on the relative activity; thus, where the The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 A solution of 500 mg. of 9m-fluorohydrocortisone and 300 mg. of pure p-toluene sulfonyl chloride in 3.5 m1. of

acetal derivative, for example, has activity of the same 75 anhydrous pyridine is warmed in the steam bath fori15 .9, minutes- After standing at room temperature forZ hours, 10 ml; of acetone is added and the mixture placed in the refrigerator for 4 hours. The resulting crystals are filtered off and washed with acetone. Recrystallization of this fraction (about 228 mg). from methanol furnishes the pure 21-pyridinium chloride, M.P. about 320-321 (dec.); [a] +200 (c. 0.22 in methanol);

Ag; 239 mp (E= 19,600)

Analysis.-Calcd. for C H O NClF (447.99): C, 65.33; H, 6.96; Cl, 7.42. Found: C, 65.48; H, 6.82; Cl, 7.37.

Concentration of the pyridine-acetone: mother liquor in vacuo to a thick sirup and addition of acetone gives after cooling an additional crop (about 21 mg.) of the pyridium chloride. For the preparation of the nitrone the twocrops'are used without further purification.

Concentration of the mother liquors to near dryness invacuo' affords after addition of acetone. and cooling about 180 mg. of 9a-fluoro-2l-chloro-A -pregnene-111e- 17a-diol-3,20-dione, M.P. about 265 (dec.), which after crystallization from methanol melts at about 275 (dec.); [e1 3 +153 (c. 0.3 dioxane);

Hi1.. 238 m (E= 16,800 A2521 l; .08 (3-keto) Analysis.-Calcd. for C H O C IF (398.89): C, 63.23; H, 7.08; CI, 8.89. Found: C, 63.25; H, 7.34; Cl, 8.44.

When the above reaction is conducted at 5-15 9afiuoro-2l-chloro-M-pregnene-l1B,l7a-diol-3,20 dione is formed exclusively.

If p-toluene sulfonyl bromide is substituted for ptoluene sulfonyl chloride in Example 1, the resulting mixture will consist of the 2l-pyridinium bromide (XIV) and the2l-bromide (VI). Furthermore, if 9a-fluorocortisone (III)-is substituted for 9a-fluorohydrocortisone, then the resulting steroids will be either a mixture of 9a-fluoro- A -pregnene-17a-o1-3J1,20-trione 21-pyridinium chloride (XVII) and 9a-fluoro 21 chloro A pregnene-l7a-ol- 3,11,20-trione (IX), or 9a fluoro-A -pregnene-l'la-ol- 3,11,20-trione 2.1-pyridinium bromide (XVIII) and 9afluoro 21 bromo A pregnene-17a-ol-3,l1,20-trione (X), depending on whether tosyl chloride (in the preparation of the first mixture) or tosyl bromide (in the preparation of the second mixture) is used.

The process of Example 1 is of general applicability and may also be employed to convert 17-unsubstituted steroids having a 21-hydroxy group to the corresponding 2l-aldo substituted derivatives. Thus, if a9a-ha1ocorticosterone or 9a-halo-dehydrocorticosterone is substituted for 9a-fluoro-hydrocortisone in Example 1, the corresponding 21-desoxycorticosterone and 21 desoxydehydrocorticosterone derivatives are formed, respectively. Similarly if a 9a-haloaldosterone, such as 9a-fluoroa'ldosterone or 90:- chloroaldosterone, is substituted'for the 9a-fluorohydrocortisone in the process of Example 1, the corresponding 21-desoxyaldosterone derivatives are produced.

EXAMPLE 2 ium chloride (XV) and 911,21-dichlor0-A pregnene-1 1B,

, I 7a-di0l-3,20-di0ne (VII) from 9a-chlorohydrocortisane (II) A solution of 500 mg. of 9ot-chlorohydrocortisone and 300 mg. p-toluenesulfonyl chloride in 3 ml. of anhydrous pyridine is heated on the steam bath for 15 minutes. A crystalline precipitate appears which is'filter'ed off and washed with acetone. It represents the desired 21-pyridinium chloride, M.P. about 287 (dec.) and is used with out further purification in the nitrone formation reaction. Concentration of the mother liquor afford an additional crop of this substance and then two crops of a lower melting substance, M.P. about 235-237 which is-recrystallized'from 95% alcohol.- Thelatter substance 10 represents 9a,2l-dichloro-M-pregnene-11p,17-diol-3,20 dione; lai +178 (c. 0.28 in absolute alcohol);

Analysis.-Calcd. for C H 0 Cl (415.34): C, 60.72; H, 6.79; Cl, 17.08. Found: C, 60.79; H, 6.70;.Cl,.16.66.

If p-toluenesulfonyl bromide is substituted for p-toluenesulfonyl chloride in Example 2,. the resulting mixture will consist of the 2l-pyridinium bromide (XVI) and the 21-bromide (VIII). Furthermore, upon the substitution of 9 -chlorocortisone (IV) for the 9a-chloro-hydrocortif sone, either a mixture of 9a-chloro-A -pregnene-17a-ol+ 3,11,20-trione 21-pyridinium chloride (XIX) and :,21- dichloro-A -pr'egnene-17a-ol-3,1l,20 trione (X1), or 90:- chloro-A -pregnene-17a-ol-3,11,20-trione 21 pyridinium bromide (XII) and 9a-chloro-2l-bromo A -pregnene-lhol-3,1'1,20-trione (XII), depending on whether tosyl chloride or tosyl bromide is used, will be tormed.

The 21-halo steroids produced by the method of Examples 1 and 2 can then be converted to the quaternary ammonium salt as illustrated by the following example using Compound V as a starting material:

EXAMPLE 3 A solution of 156 mg. of 9a-fluoro-2l-chloro-M-pregnene-l1fl,17a-diol-3,20-dione in 3 ml. of dry pyridine is heated on the steam'bath for 30 minutes and after cooling 5' ml. of acetone is added. Cooling produced a crop of crystals (about 123 mg.), M.P. about 3l932l (dec.), which represent the 2l-py'ridinium chloride. From the mother liquors about 32 mg. of starting material M.P. 263 (dec.) is recovered. Since the tertiary base is eliminated in the next step of the process, the exact chemical composition of the base is of no importance, so that any other tertiary base may be substituted for pyridine in the processesof the above examples to yield other quaternary ammonium salts. Examples of such bases include the lutidines, the coIIidines the tri(lower alkyl) amines (e.g. tr'imethylamine andtriethylamine), N-alkylated piperidine, etc.

The formation of the nitrones in the next step of the process of this invention is illustrated by the following examples, using p-nitrosodimethyl aniline as a source of the nitroso reactant:

EXAMPLE 4 9a-fluoro-A -pregn'ene-115,1 7 a-diol-3,20-dione 21 -(p-d1lmethylaminophenyl) -nitr0ne (XXI) from Qua-fluoro- Atlpregnene 1119,1704 dial-3,20-dione 21-pyridinium chloride (XIII) To a warm solution of 250 mg. (0.52 millimole) of 9a fluoro A pregnene-l l 8,17a-di01-3 ,20-dione 2l-pyridinium chloride in 7 ml. of methanol and 4.5 ml. water is added 89 mg. (0.58 millimole) of p-nitrosodimethyl aniline and shortly thereafter a solution of 55 mg. of potassium bicarbonate (0.55 millimole) in 0.7 ml. of water. The mixture is gently warmed on a steam bath and then allowed to remain in the refrigerator overnight. The resulting red crystals (about mg.) are filtered off, washed with 1:1 methanol-Water and the mother liquors concentrated in vacuo. An additional crop (about 47 mg.) is obtained in this manner. The nitrone is used in the preparation of the aldehyde without further purification. For analysis the unstable nitrone is recrystallized from methanol, M.P. about 226 (dec.);

mg, 240 m (e=25,000), 304 mp (e=9,400) and 415' m (e=11,850)

Analysia-Calcd. for C,,H,,O,N,F (512.61): C, 67.94; H, 7228;" N, 5.57." Found: c, 68.87; H, 7.36; N, 6.28.

1 1 7 EXAMPLE 9u-chl0r0-A -pregnene-11B,17a-di0l-3,20-dione 21 p-dimethylaminophenyl) -nitrone (XXII) from 9oc-chl0r0- A -pregnene-I1fi,17a-di0l 3,20 dione 21 -pyridinium chloride (XV) To a warm suspension of 140 mg. of 9a-chloro-A pregnene-lle,17a diol-3,20-dione 21-pyridinium chloride in 3.8 ml. of methanol and 2.4 ml. water is added 47 mg. of p-nitrosodimethyl aniline. When the latter has dissolved a solution of 30 mg. of potassium bicarbonate in 0.38 ml. of water is added and the mixture warmed on the steam bath until all the pyridinium salt has dissolved, and has been replaced by the red crystals of the nitrone. The reaction mixture is then cooled and allowed to remain in the refrigerator for one hour. The crystals are filtered and washed with 50% methanol-water and finally with water. The yield of nitrone is about 104 mg, M.P. about 206. The substance is used in the preparation of the aldehyde without further purification.

In an analogous manner the pyridinium bromides (XIV and XVI) can be converted to the 9a-fluoro and Qua-chloro derivatives, respectively.

If 9a-fluoro-A -pregnene17a-ol-3,11,20-trione 2l-pyridinium chloride (XVII) or bromide (XVIII) is substituted for the pyridinium chloride in Example 4, 9a-fiuoro- A -pregnene-l7a-ol-3J1,20-trione 21 (p-dimethylaminophenyl)-nitrone (XXIII) is formed. Similarly, if 9achlioro-A -pregnene-17 oz-Ol-3 ,11,20-trione 2 l -pyridinium chloride (XIX) or bromide (XX) is substituted for the pyridinium chloride in Example 5, '9et-chloro-A -pregnene-17a-ol-3,1 1,20-trione 21-(p-dimethylaminophenyl) nitrone (XXIV) is produced. Analogously, the quaternary ammonium salts of the corticosterone, dehydrocorticosterone and aldosterone derivatives are converted to the corresponding nitrones.

Although the above examples employ p-nitrosodimethyl aniline as the source of the nitroso radical, any other'aromatic nitroso-containing compound (such as nitroso benzene) may be used instead, since in the next step of the process the nitroso group is replaced by an aldo or acetalized aldo substituent.

The nitrone is then converted either to the 21-acetalized aldo or the free 21-aldo as illustrated by the following examples:

EXAMPLE 6 To a suspension of 120 mg. of 9e-fluoro-A -pregnene- 113,170 diol 3,20 dione(21 p dimethylaminophenyD-nitrone in 2 ml. of acetone is added at room temperature 1 ml. of 2 N aqueous hydrochloric acid. Gentle agitation causes the nitrone to dissolve rapidly to form a yellow solution. After centrifugation of some insoluble matter 4 ml. of water is added, which causes the aldehyde hydrate to crystallize in fine needles. After one hour at 5 the crystals are separated from the mother liquors and washed thoroughly with water. The resulting crystals (about 81.5 mg), after recrystallization from acetone-water melt at about 190-491",

[@ +126 (c. 0.48 in methanol);

M33, 238 m, Fiasco x2 5 30-32,. (OH), 5.86. (20-keto), 6.15,. (4-keto) Analysis.Calcd. for C I-I O RH O (396.44): C, 63.62; H, 7.37; F, 4.79. Found: C, 63.71; H, 7.18; F, 4.87.

9 fluoro A pregnene 11 3.170: diol 3,20-

cortisone acetate in the rat liver glycogen assay-midis; about equal in activity to desoxycorticosterone in the sodium retention assay in the rat.

To prove its 20-keto-21-aldo structure, the steroid is converted into the quinoxaline as follows:

A solution of 20 mg. of the 2l-a1dehyde hydrate and 8 mg. of o-phenylenediamine in 2 ml. of alcohol is refluxed for one hour. On concentration and cooling about 14.6 mg. of the desired quinoxaline is obtained, which after recrystallization from 95 alcohol melts at about 308-310";

9a chloro A pregnene 1119,17; diol 3,20 dione 21 -al hydrate (XXVI) from 9a-chloro-A -pregnene- 115,17: diol 3,20 dione 21 (p dimethylaminaphenyl)-nitr0ne (XXII) 9oi-chloro-A -pregnene-l1fi,17a-diol-3,20-dione 21-(pdimethylaminophenyl)-nitrone is converted to 9a-chloro-' M-pregnene-l1B,17u-dio1-3,20-dlone-21-al' hydrate as described in Example 6 for the corresponding fluoro compound.

The pure 9a chloro A pregnene-l1p,17 x-diol'3,20- dione-21-al hydrate, after recrystallization from dilute acetone, has the following properties: M.P. greater than 345 with darkening at [0:]5 +132 (c. 0.35 in methanol);

mg, 240 mp (e=18,400);7\21. 2.92.1, 3.05-3.09, (OH), 5.85,. (20-keto), 6.12,. (3-keto) Analysis.-Calcd. for C 1H2705C1.H2O (412.9o): C, 61.08; H, 7.08; Cl, 8.59. ,Found: C, 61.43; H, 6.73; Cl, 8.66.

90: chloro A pregnene 1113.170: diol 3,20 dione-21-al hydrate shows about /3 the activity of cortisone acetate in the rat liver glycogen assay. It is about 3 times as active as desoxycorticosterone in the sodium retention assay in the rat.

The ZI-aldehyde hydrate can be converted into the bisulfite adduct and the quinoxaline as described in Example 6 for the corresponding 9a-fluoro compound.

If 9a-fluoro-A -pregnene-17a-ol-3,11,20-trione 21-(pdimethyl aminophenyl)-nitrone (XXIII) is substituted for the 9u-fiuoro-A -pregnene-11B,17a-diol-3,20-dione 21- (p-dimethylaminophenyl)-nitrone of Example 6, or if 9echloro-A -pregnene-17a-ol-3,11,20-trione 21-(p-dimethylaminophenyl) -nitrone (XXIV) is substituted for the 90.- chloro-lIfl-hydroxy derivative of Example 7, then 90:- fluoro A pregnene 17a o1 3,11,20 trione 21 al hydrate (XXVII) and 9e-ch1oro-A -pregnene-171-01- 3,11,20-trione-21-al hydrate (XXVIII) are formed, respectively. Similarly, by substituting the ZI-(p-dimethylaminophenyl) nitrone derivatives of 9a fluoro (or chloro)-A pregnene-l 1p-o1-3,20-dione, or of 9a-fluoro (or chloro)-A -pregnene-3,11,20-trione, or of 9a-fluoro (or chloro)-A -pregnene-1 1 8ol-3,20-dione-18-al for the nitrone employed in Example 6, 9ot-fluoro (or chloro)-A pregnene-l1 8-ol-3,20-dione-21-al hydrate, and 9u-fluoro (or chloro) -A -pregnene-1 1 8-ol-3,20-dione-18,21-diol 21,- hydrate, respectively, are produced.

The aldehyde hydrates produced by the methods of Examples 6 and 7 can then be converted to their social diorie-Zl-al hydrate possesses about A the activity of 75 derivatives by treatment with the desired alcohol in the eerie-ere presence of an acid. This processis illustrated by the following example:

EXAMPLE 8' 9a fluoro A pregnene 115,17 diol 3,20 dione- 21-al dimethyl acetal (XXIX) from 9a-flu0r0-A -pregnene-I1p,17a-diol-3,20-dione-21-al hydrate (XXV) A solution of 100 mg. of 9a-fluoro-A -pregnene-11fl, 17a-diol-3,20-dione-21-al hydrate in 10 ml. of 1% methanolic hydrogen chloride is allowed to stand at room temperature for 24 hours. An excess of sodium bicarbonate solution is then added and the solution is concentrated in vacuo. The residual mixture is extracted with chloroform, the cholorform solution washed with water and the solvent evaporated in vacuo. The resulting residue consists of the desired dimethyl acetal.

By substituting 9a-ch1oro-A -pregnene-115,17a-diol-3, 20-dione-21-a1 hydrate (XXVI), or 9a-fluoro-A -pregnene-l7a-o1-3,11,20-t1ione-21 a1 hydrate (XXVII), or 90:- chloro-M-pregnene-17a-ol-3,11,20-trione-21 al hydrate (XXVIII) for the aldehyde in Example 8, the corresponding dimethyl acetals (compounds XXX to XXXII, respectively) are obtained. Similarly, the hydrates of the aldehyde derivatives of 9a-fluoro and 9a-chloro corticosterone, dehydrocorticosterone, and aldosterone, can be converted to their respective dimethyl acetal derivatives by the method of Example 8.

Furthermore, by substituting 10 ml. of 1% ethanolic hydrogen chloride for the methanolic hydrogen chloride in Example 8, 9a-fiuoro-A -pregnene-11B,17a-diol-3,20- dione-21-al-diethyl acetal is produced. Similarly, by substituting other alkanols for methanol in Example 8, the corresponding 2l-dialkyl acetal derivatives are formed. Thus, n-propanol yields 9a-fluoro-A -pregnene-115,17- diol-ol-3,20-dione-2l-al-di-n-propyl acetal, and n-butanol yields 9a-fluoro-A -pregnene-11p,17a diol-3,20-dione-21- al-di-n-butyl acetal, while ethylene glycol yields 9a-fluoro- M-pregnene-l lfl,l7a-diol-3,20-dione-2l-al-ethylene acetal.

Moreover, the 21-acetal'scan be produced directly'from the nitrones as illustrated by the following example:

EXAMPLE 9 9u-flu0ro-A -pregnene-1113,17a-diol-3,20-dione 21-al dimethyl-acetal (XXIX) from9a-fluor0-ALpregnene-IIfl, 17a dial 3,20 dione 21 (p dimethyldminophenyl)-nitrne (XXI) extracted with dilute bicarbonate and water and after drying over sodium sulfate, is evaporated to dryness in vacuum. The residue represents the dimethyl acetal of 9a-fluoro-A -pregnene-l 13,18a-di01-3 ,20-dione-2 1 -al.

The aldehydes can be converted to their diesterified derivatives by treatment with an acid anhydride in a tertiary base, asvillustrated by the following example:

' EXAMPLE 1o 9a-fluoro-A -pregnene-l 1p,17u-di0l-3,20-dione-21 -al 21 -didione-Zl -al hydrate (XXV) A solution of mg. of 9a-fluoro-A -pregnene-l15,170:- diol-3.20-dione-2l-al hydrate in 0.5 ml. of acetic anhydride and 0.5 ml. of pyridine is allowed to stand at room temperature for 18 hours. Evaporation of the reagents 14 substituted for acetic anhydride in the above example, the, corresponding diester is formed.

Although the 9a-bromo and 9a-iodo-2l-aldo or-acetalized or diesterified aldo steroids of this invention can be prepared by the methods of Examples 1 through 10, in some instancesit may be preferable to form these halide derivatives indirectly from the corresponding 9a-chloro Ila-.hydroxy 21-aldo or acetalized derivatives by way of the 95,11fi-oxido intermediates. Thus, the 9a-chloro 11B- hydroxy 21-aldo (or acetalized aldo) derivatives are re acted with a salt of a strong base and a weak acid, such as an alkali metal carbonate or bicarbonate (i.e. potassium carbonate) or an alkali metal lower alkanote (i.e. potassium acetate), and the corresponding 9,8,115-oxido compound, thus formed, is then reacted with a hydrogen halide (e.g hydrofluoric acid, hydrochloride acid, hydrobromic acid or" hydroiodic acid) to form the 9a-halo 11B,17a-dihydroxy 21-aldo (or acetalized aldo) derivative. The series of steps can be represented by the following'schematic analysis and examples:

XXXIII B=H X-XXIV B=CHa EXAMPLE 11 913,1lp-oxido-M-pregnene-l 7a-ol-3,20-di0ne-21-al hydrate (XXXIII) from 9a-cIzl0r0-A -pregnene-1 15,1 7a-di0l- 3,20-dione-21-al hydrate (XXVI) To a solution of mg. of 9a-chloro-At-pregnene- 11,3,l7a-diol-3,20-dione-2l-al hydrate in 10 ml. of methanol is added a solution of 100 mg. of potassium carbonatein 0.5 ml. of oxygen-free water. Nitrogen is passed through the resulting solution for 5 minutes and the mixture is allowed to remain at room temperature for three hours. Acetic acid is added to neutralize the carbonate and after the addition of 5 ml. water the methanol is removing in vacuo. The remaining aqueous suspension is extracted with chloroform, the chloroform extract washed with water and dried over sodium sulfate. Evaporation of the solvent leaves a residue of the desired 913,1 lB-epoxide.

In a similar manner, by using 9a-chloro-A -pregnene- 113,17u-diol-3,20-dione-21-al dimethylacetal (XXX) as the starting material, 95,1lfl-oxido-A -pregnene-17a-ol 3,20-dione-21-al dimethylacetal (XXXIV) is formed.

15 EXAMPLS 12 To a solution of 25 mg. of 93,11B-oxido-M-pregnene- 17a-ol-3,20-dione-2l-al in 1 ml. of chloroform is added with shaking at room temperature 0.04 ml. 30% hydrobromic acid in glacial acetic acid. After 10 minutes, 10 ml. of chloroform is added, and the mixture is extracted with dilute sodium bicarbonate and with water. The chloroform solution is dried over sodium sulfate, and evaporated to dryness in vacuo; and the residue, representing 9a-bromo-A -pregnene-l1B,17a-diol 3,20 dione- 21-al is crystallized from acetone.

In a similar manner, by substituting 60% aqueous hydroiodic acid for hydrobromic acid in Example 12, the corresponding 9oc-i0d0 compound (X)Q(VI) is formed.

The 9a-bromo and 9oc-i0d0 acetalized 2l-aldehydes or diesterified 21-aldehydes can be prepared from the 90;- bromo and 9u-iodo 2l-aldo derivatives by the methods of Examples 8 or 10, respectively, or the 9a-bromo and 9a-i0d0 acetalized 21-aldehydes can be prepared directly from the 9,6,l1B-oxido acetalized 2l-aldehyde (XXXlV) by the method of Example 12. Furthermore, the 90:- bromo or 9a-iodo 1lfi-hydroxy 2l-aldo derivatives can be oxidized to the 9u-bromo or 9a-i0d0 ll-keto 21-a1d0 derivatives by reaction with chromic acid.

These 9a-bromo and 9a-iodo 2l-aldo steroids, aside from their activity as glucocorticoids and mineralocorticoids, have an added utility as intermediates in the preparation of the known 9a-dehalo analogues. Thus, the 9a-bromo and 9a-i0d0 steroids may be reduced by treatment with usual reducing agents, such as zinc in glacial acetic acid, to remove the 9u-halo radical and form the corresponding 9-unsubstituted derivatives.

We claim:

1. 21-acetalized 9a-chloro-A -pregnene 115,170: diol- 3,20-dine-21-al.

2. 21-acetalized 9a-chloro-A-pregnene-1711-01-3,11,20- trione-21-al.

3. 9a-chloro-A -pregnene-l1fl,17a-diol-3,20 dione 21- al hydrate.

4. 9a-chloro-A -pregnene-17a-ol+3,11,20 trione 21-a1 hydrate.

5. 913,11/3-oxido-A -pregnene-17u-ol-3,20-dione-2l-al.

6. The 21-di(lower alkanoic acid) ester of 9a-chloro- A -pregnene-1 1 8,17a-diol-3,20-dione-2l-al.

7. The 21-di(lower alkanoic acid) ester of 9a-chloro- A -pregnene-l7a-ol-3J 1,20-trione-21-al.

8. A steroid selected from the group consisting of those of the formula 1 and individually R is hydrogen, R'" is p-hydroxy and to! gether R" and R is keto; X is an a-halogen group; and Y is selected from the. class consisting of wherein B is a radical of the class consisting of saturated aliphatic and aralkyl radicals, and B' is a saturated dival- 10 cut aliphatic radical.

9. 2l-acetalized 9a-halo-A -pregnene-11fi-ol-3,20-dione 18,21-dial.

'10. A steroid selected from the class consisting of those of the formula 15 O=CH CH=O and

CH=O

so .I a-

as p I p V p wherein individually R" is hydrogen, R'" 1s fl-hydroxy 40 and together R" and R'" is keto; X is an u-halogen group;'and the hydrates thereof.

11. 9a-halo-A -pregnene-llibel-3,20 dione 18,21-dial hydrate. 1 v

12. A steroid selected from the class consistingof those of the formulae and wherein individually R" is hydrogen, R' is p-hydroxy and together R" and R" is keto; and Z is selected from the class consisting of -CH=O, -CH(OH) and wherein B is a radical of the class consisting of saturated aliphatic and aralkyl radicals, and B is a saturated divalent aliphatic radical.

References Cited in the file of this patent 10 FOREIGN PATENTS 00GB 716,974 Great Britain Oct. 20, 1954 OTHER REFERENCES Fried et al.: J. Am. Chem. Soc., vol. 75, 2273 (1953).

Fried et al.: I. Am. Chem. Soc. vol. 76, 1455 (1954).

Rogers et al.: I. Am. Chem. Soc., vol. 74, 2947 (1952).

Simpson et al.: Helv. Chim. Acta, Vol. 37, pp. 1170, 1171 and 1197.

Hershberg et al.: J. Am. Chem. Soc., vol. 74, 3850 UNITED STATES PATENTS (1952) Pfister et a1 May 10, 1955 Mattox: J. Am. Chem. Soc., vol. 74, pp. 4330, 4341 Leanza et a1 Oct. 11, 1955 and 4346. Hogg et a1 Jan. 10, 1956 15 Borman et al.: Proc. Soc. Exp. Bio. Med., vol. 86, pp. Tishler Feb. 28, 1956 570-573. Fried Nov. 4, 1958 

8. A STERIOD SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA 